Project Summary Abstract Cancer is the leading cause of death in HIV-infected individuals on combination antiretroviral therapy (cART) in the United States and globally. This is because people infected with HIV can expect a near normal life on cART and overall mortality is determined by the same diseases as in the general population. Nevertheless, certain cancers occur much more frequently in HIV-infected individuals than in HIV-negative persons. These cancers include the AIDS-defining cancers, Kaposi sarcoma (KS) and a variety of lymphomas, including primary effusion lymphoma (PEL), which is associated with infection with Kaposi's sarcoma-associated herpesvirus and non-Hodgkin lymphomas, which are associated with infection by Epstein-Barr virus. In fact, KS is the leading cancer in the HIV-positive population today. Furthermore, as the HIV-positive cohort ages they are at an increasing risk of developing both AIDS-defining cancers (ADCs) as well as non-AIDS defining cancers (NADCs). This application is in response to RFA-CA-17-030 on HIV/AIDS and the Tumor Niche. We propose to understand the impact of HIV infection on the microenvironment that surrounds the ADCs, Kaposi sarcoma and non-Hodgkin lymphoma. We will investigate the impact of HIV viral proteins on tumor progression and angiogenesis of ADCs using novel mouse models of pathogenesis and tumorigenesis. We will also explore the mechanisms for the increased rate of development of cancers in the HIV infected population.